Abstract
Prolonged cigarette smoking (CS) causes chronic obstructive pulmonary disease (COPD), a prevalent serious condition that may persist or progress after smoking cessation. To provide insight into how CS triggers COPD, we investigated temporal patterns of lung transcriptome expression and systemic metabolome changes induced by chronic CS exposure and smoking cessation. Whole lung RNA-seq data was analyzed at transcript and exon levels from C57Bl/6 mice exposed to CS for 1- or 7 days, for 3-, 6-, or 9 months, or for 6 months followed by 3 months of cessation using age-matched littermate controls. We identified previously unreported dysregulation of pyrimidine metabolism and phosphatidylinositol signaling pathways and confirmed alterations in glutathione metabolism and circadian gene pathways. Almost all dysregulated pathways demonstrated reversibility upon smoking cessation, except the lysosome pathway. Chronic CS exposure was significantly linked with alterations in pathways encoding for energy, phagocytosis, and DNA repair and triggered differential expression of genes or exons previously unreported to associate with CS or COPD, including Lox, involved in matrix remodeling, Gp2, linked to goblet cells, and Slc22a12 and Agpat3, involved in purine and glycerolipid metabolism, respectively. CS-induced lung metabolic pathways changes were validated using metabolomic profiles of matched plasma samples, indicating that dynamic metabolic gene regulation caused by CS is reflected in the plasma metabolome. Using advanced technologies, our study uncovered novel pathways and genes altered by chronic CS exposure, including those involved in pyrimidine metabolism, phosphatidylinositol signaling and lysosome function, highlighting their potential importance in the pathogenesis or diagnosis of CS-associated conditions.
Highlights
Chronic obstructive pulmonary disease (COPD) is a common, heterogeneous group of lung diseases characterized by airflow obstruction due to chronic bronchitis, emphysema, or small airways disease [1]
These functional changes are consistent with a loss of lung elastance that characterizes emphysema-like lung injury in Cigarette smoke (CS)-susceptible strains of mice [5]
Since each CS-exposure group was age-matched for a control air control (AC)-exposed group, we had the opportunity to note that aging had a significant effect on lung compliance in these C57Bl/6 female mice (Fig 1)
Summary
Chronic obstructive pulmonary disease (COPD) is a common, heterogeneous group of lung diseases characterized by airflow obstruction due to chronic bronchitis, emphysema, or small airways disease [1]. Studies using diverse methodologies that assess changes in mouse lungs following CS exposure have identified mechanisms driving the development of COPD in smokers, including airway inflammation, oxidative stress, an imbalance of proteinases/anti-proteases, autoimmune responses, defective autophagy and injurious apoptosis of alveolar cells, ineffective clearance of apoptotic cells by macrophages, disrupted histone acetylation/deacetylation, and accelerated lung aging leading to failure of lung maintenance and repair [1,3]. Previous gene expression studies of CS-exposed mice have only moderate reproducibility, suggesting an influential role of various exposure protocols, technologies, analytical methods, and mouse strains. These gene expression studies have primarily utilized microarray technology, which has limitations compared to next-generation sequencing techniques due to sparser sampling of probes along the genome and reduced sensitivity to low expression levels of genes [4]. The experimental design, differential gene expression, and gene set enrichment of previous relevant gene expression studies are summarized in the Online Supplement (Tables A-C in S2 File)
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